No Effect of One-Year Treatment with Indomethacin on Alzheimer's Disease Progression: A Randomized Controlled Trial

Contains fulltext : 71117.pdf (publisher's version ) (Open Access)BACKGROUND: The objective of this study was to determine whether treatment with the nonselective nonsteroidal anti-inflammatory drug (NSAID) indomethacin slows cognitive decline in patients with Alzheimer's disease (AD). METHODOLOGY/PRINCIPAL FINDINGS: This double-blind, randomized, placebo-controlled trial was conducted between May 2000 and September 2005 in two hospitals in the Netherlands. 51 patients with mild to moderate AD were enrolled into the study. Patients received 100 mg indomethacin or placebo daily for 12 months. Additionally, all patients received omeprazole. The primary outcome measure was the change from baseline after one year of treatment on the cognitive subscale of the AD Assessment Scale (ADAS-cog). Secondary outcome measures included the Mini-Mental State Examination, the Clinician's Interview Based Impression of Change with caregiver input, the noncognitive subscale of the ADAS, the Neuropsychiatric Inventory, and the Interview for Deterioration in Daily life in Dementia. Considerable recruitment problems of participants were encountered, leading to an underpowered study. In the placebo group, 19 out of 25 patients completed the study, and 19 out of 26 patients in the indomethacin group. The deterioration on the ADAS-cog was less in the indomethacin group (7.8+/-7.6), than in the placebo group (9.3+/-10.0). This difference (1.5 points; CI -4.5-7.5) was not statistically significant, and neither were any of the secondary outcome measures. CONCLUSIONS/SIGNIFICANCE: The results of this study are inconclusive with respect to the hypothesis that indomethacin slows the progression of AD

Cytokine and Anti-Inflammatory Drug Effects on Brain Trauma and Alzheimer’s Disease Pathology in Transgenic Mice

There is a continuous interaction between neurons, glia and inflammatory cells in the normal brain that is exacerbated following trauma or neurodegenerative disease. Cytokines mediate many of these interactions in injury and disease, and they may also play key roles in the developing and normal adult brain. Experiments using mice with targeted mutations in the gene for one of these cytokines, leukemia inhibitory factor (LIF), demonstrate that this protein is required for appropriate cell and behavioral responses to trauma in the nervous system. We find that LIF is induced by physical injury or chemically-induced inflammation, and in the absence of this cytokine, neuronal, astrocytic, microglial, neutrophil, macrophage and pain responses to these insults are strikingly altered. The specific effects of LIF deficiency depend critically on the site and type of injury, however. The inflammatory response can also be important in the establishment and/or progression of neurodegenerative disease. To study this we are using a transgenic mouse model of Alzheimer’s disease (AD). Preliminary results indicate that stressing the animals can strongly up-regulate the microglial reaction around senile plaques